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Fluids and Barriers of the CNS Nov 2020The blood-brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain's metabolic activity as well as... (Review)
Review
The blood-brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain's metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain-blood interface. We also explained the role of shear stress in maintaining BBB integrity. Furthermore, we elaborated on the clinical aspects that correlate between BBB disruption and different neurological and pathological conditions. Finally, we discussed several biomarkers that can help to assess the BBB permeability and integrity in-vitro or in-vivo and briefly explain their advantages and disadvantages.
Topics: Biological Transport; Biomarkers; Blood-Brain Barrier; Brain Diseases; Humans
PubMed: 33208141
DOI: 10.1186/s12987-020-00230-3 -
Neural Plasticity 2021The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain's... (Review)
Review
The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain's extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specific targeting systems in material delivery as a future approach that assists in combinatorial therapy or nanotherapy to destroy or modify this barrier in pathological conditions such as brain tumors and brain stem cell carcinomas.
Topics: Animals; Biomarkers; Blood-Brain Barrier; Brain; Humans
PubMed: 34912450
DOI: 10.1155/2021/6564585 -
Brain Research Aug 2022The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic... (Review)
Review
The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic microenvironment. All constituent cell types play indispensable roles in the BBB's integrity, and other structural BBB components, such as tight junction proteins, adherens junctions, and junctional proteins, can control the barrier permeability. Regarding the need to exchange nutrients and toxic materials, solute carriers, ATP-binding case families, and ion transporter, as well as transcytosis regulate the influx and efflux transport, while the difference in localisation and expression can contribute to functional differences in transport properties. Numerous chemical mediators and other factors such as non-physicochemical factors have been identified to alter BBB permeability by mediating the structural components and barrier function, because of the close relationship with inflammation. In this review, we highlight recently gained mechanistic insights into the maintenance and disruption of the BBB. A better understanding of the factors influencing BBB permeability could contribute to supporting promising potential therapeutic targets for protecting the BBB and the delivery of central nervous system drugs via BBB permeability interventions under pathological conditions.
Topics: Biological Transport; Blood-Brain Barrier; Brain; Humans; Permeability; Tight Junction Proteins; Tight Junctions
PubMed: 35568085
DOI: 10.1016/j.brainres.2022.147937 -
Nature Reviews. Cancer Jan 2020For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the... (Review)
Review
For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumours as well as brain metastases. In this Review, we highlight the cellular and molecular components of the blood-brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumours are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood-tumour barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of molecules. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging molecular, cellular and physical strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biology approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.
Topics: Animals; Antineoplastic Agents; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Combined Modality Therapy; Drug Delivery Systems; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Precision Medicine; Tumor Microenvironment
PubMed: 31601988
DOI: 10.1038/s41568-019-0205-x -
Annual Review of Cell and Developmental... Oct 2019The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A... (Review)
Review
The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A unique feature of the central nervous system (CNS) vasculature is the blood-brain barrier (BBB). The BBB regulates substance influx and efflux to maintain a homeostatic environment for proper brain function. Here, we review the development and cell biology of the BBB, focusing on the cellular and molecular regulation of barrier formation and the maintenance of the BBB through adulthood. We summarize unique features of CNS endothelial cells and highlight recent progress in and general principles of barrier regulation. Finally, we illustrate why a mechanistic understanding of the development and maintenance of the BBB could provide novel therapeutic opportunities for CNS drug delivery.
Topics: Animals; Astrocytes; Basement Membrane; Biological Transport; Blood-Brain Barrier; Brain; Central Nervous System; Endothelial Cells; Homeostasis; Humans; Leukocytes; Neurovascular Coupling; Pericytes; Tight Junctions; Transcytosis; Wnt Signaling Pathway
PubMed: 31299172
DOI: 10.1146/annurev-cellbio-100617-062608 -
The Journal of Experimental Medicine Apr 2020The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control the movement of ions, molecules, and cells... (Review)
Review
The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control the movement of ions, molecules, and cells between the blood and the parenchyma. This "blood-brain barrier" is initiated during angiogenesis via signals from the surrounding neural environment, and its integrity remains vital for homeostasis and neural protection throughout life. Blood-brain barrier dysfunction contributes to pathology in a range of neurological conditions including multiple sclerosis, stroke, and epilepsy, and has also been implicated in neurodegenerative diseases such as Alzheimer's disease. This review will discuss current knowledge and key unanswered questions regarding the blood-brain barrier in health and disease.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Central Nervous System; Humans
PubMed: 32211826
DOI: 10.1084/jem.20190062 -
Inflammation Dec 2021Sepsis is a life-threatening clinical condition caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is a common but poorly... (Review)
Review
Sepsis is a life-threatening clinical condition caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis, which is associated with increased morbidity and mortality. SAE clinical presentation may range from mild confusion and delirium to severe cognitive impairment and deep coma. Important mechanisms associated with SAE include excessive microglial activation, impaired endothelial barrier function, and blood-brain barrier (BBB) dysfunction. Endotoxemia and pro-inflammatory cytokines produced systemically during sepsis lead to microglial and brain endothelial cell activation, tight junction downregulation, and increased leukocyte recruitment. The resulting neuroinflammation and BBB dysfunction exacerbate SAE pathology and aggravate sepsis-induced brain dysfunction. In this mini-review, recent literature surrounding some of the mediators of BBB dysfunction during sepsis is summarized. Modulation of microglial activation, endothelial cell dysfunction, and the consequent prevention of BBB permeability represent relevant therapeutic targets that may significantly impact SAE outcomes.
Topics: Animals; Blood-Brain Barrier; Capillary Permeability; Cytokines; Endothelial Cells; Endotoxins; Humans; Inflammation Mediators; Microglia; Neuroinflammatory Diseases; Sepsis-Associated Encephalopathy; Signal Transduction
PubMed: 34291398
DOI: 10.1007/s10753-021-01501-3 -
Molecular Psychiatry Jun 2022The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain... (Review)
Review
The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain parenchyma. Moreover, the BBB prevents unwanted toxins and pathogens from entering the brain. This barrier, however, breaks down with age and further disruption is a hallmark of many age-related disorders. Several drugs have been explored, thus far, to protect or restore BBB function. With the recent connection between the BBB and gut microbiota, microbial-derived metabolites have been explored for their capabilities to protect and restore BBB physiology. This review, will focus on the vital components that make up the BBB, dissect levels of disruption of the barrier, and discuss current drugs and therapeutics that maintain barrier integrity and the recent discoveries of effects microbial-derived metabolites have on BBB physiology.
Topics: Biological Transport; Blood-Brain Barrier; Brain; Homeostasis
PubMed: 35361905
DOI: 10.1038/s41380-022-01511-z -
Biomaterials Dec 2019Increasing attention has been paid to the diseases of central nervous system (CNS). The penetration efficiency of most CNS drugs into the brain parenchyma is rather... (Review)
Review
Increasing attention has been paid to the diseases of central nervous system (CNS). The penetration efficiency of most CNS drugs into the brain parenchyma is rather limited due to the existence of blood-brain barrier (BBB). Thus, BBB crossing for drug delivery to CNS remains a significant challenge in the development of neurological therapeutics. Because of the advantageous properties (e.g., relatively high drug loading content, controllable drug release, excellent passive and active targeting, good stability, biodegradability, biocompatibility, and low toxicity), nanomaterials with BBB-crossability have been widely developed for the treatment of CNS diseases. This review summarizes the current understanding of the physiological structure of BBB, and provides various nanomaterial-based BBB-crossing strategies for brain delivery of theranostic agents, including intranasal delivery, temporary disruption of BBB, local delivery, cell penetrating peptide (CPP) mediated BBB-crossing, receptor mediated BBB-crossing, shuttle peptide mediated BBB-crossing, and cells mediated BBB-crossing. Clinicians, biologists, material scientists and chemists are expected to be interested in this review.
Topics: Animals; Blood-Brain Barrier; Central Nervous System Diseases; Clinical Trials as Topic; Disease Models, Animal; Drug Delivery Systems; Humans; Nanostructures
PubMed: 31546096
DOI: 10.1016/j.biomaterials.2019.119491 -
Cellular & Molecular Immunology Nov 2021The vascular blood-brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the... (Review)
Review
The vascular blood-brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the presence of systemic inflammation and infection to the brain to enable a protective sickness behavior response. With increasing degrees and duration of systemic inflammation, the vascular blood-brain barrier becomes more permeable to solutes, undergoes an increase in lymphocyte trafficking, and is infiltrated by innate immune cells; endothelial cell damage may occasionally occur. Perturbation of neuronal function results in the clinical features of encephalopathy. Here, the molecular and cellular anatomy of the vascular blood-brain barrier is reviewed, first in a healthy context and second in a systemic inflammatory context. Distinct from the molecular and cellular mediators of the blood-brain barrier's response to inflammation, several moderators influence the direction and magnitude at genetic, system, cellular and molecular levels. These include sex, genetic background, age, pre-existing brain pathology, systemic comorbidity, and gut dysbiosis. Further progress is required to define and measure mediators and moderators of the blood-brain barrier's response to systemic inflammation in order to explain the heterogeneity observed in animal and human studies.
Topics: Animals; Blood-Brain Barrier; Brain Diseases; Dysbiosis; Gene-Environment Interaction; Humans; Infections; Inflammation; Neurons; Signal Transduction
PubMed: 34594000
DOI: 10.1038/s41423-021-00757-x